Diseases of the posterior segment of eye which includes age related macular degeneration (AMD) and retinitis pigmentosa (RP) are the leading cause of blindness in United States. (Jager et al., N ENGL J MED, 2008. 358(24): 2606-17). Currently, about 8 million individuals are suffering from AMD in the United States and by 2020 this number is expected to reach 12 million. (Jager et al.; Friedman et al. Arch Ophthalmol, 2004. 122(4): p. 564-72). Dry form of AMD (Dry AMD) associated with chronic oxidative stress and inflammation accounts for 90% of AMD cases. (Libby et al. Adv Exp Med Biol, 2010. 664: p. 403-9; Stuen. Generations, 2003. 27: p. 8-14). On the other hand RP is a genetically inherited disease caused by more than 50 different gene mutations. (Ohguro, H., et al., Nihon Ganka Gakkai Zasshi, 2002. 106(8): p. 461-73; Dryja, et al., Nature, 1990. 343(6256): p. 364-6.) Around 1.5 million people worldwide currently suffer from RP. (Hartong, et al., Lancet, 2006. 368(9549): p. 1795-809).
The unique anatomy and physiology of the eye is a major hurdle in the advancement of drug therapeutic for the back of the eye including retinal degenerative diseases. (Kompella et al., Ther Deliv. 1(3): p. 435-56). Topical routes of administration are inefficient in delivering drugs to the back of the eye because of the presence of various static barriers (cornea, conjunctiva, and sclera among others tissues) and dynamic barriers (blinking, tear film, tear turn over, and induced lacrymation). (Gaudana, R., et al., Ocular drug delivery. Aaps J, 2010. 12(3): p. 348-60; Thrimawithana et al. Drug Discov Today, 2011. 16(5-6): p. 270-7). On the other hand blood retinal barrier (BRB), systemic degradation, systemic side effects, and low concentrations at target site are major challenges for the intravenous route. Other routes such as intra cameral, periocular, subretinal have their own subset of problems sharing some issues in common with topical and systemic route of administration (Baid et al. Drug Development and the back of the eye. ed. Kompella UB. 2010, p. 409-448: Springer). Local delivery such as an intravitreal injection places the drug to close proximity to the retina (the target tissue for retinal degenerative diseases) and thus is the most effective route in delivering drug to retina. However, frequent intravitreal injections of the drug leads to various complications such as retinal detachment, retinal hemorrhage, endopthalmitis, increased intraocular pressure, and not to mention patient compliance and infections. (Peyman et al. Retina, 2009. 29(7): p. 875-912; Wu et al. Semin Ophthalmol, 2009. 24(2): p. 100-5). Thus there is a need of for compositions and delivery system that can extend the retention of drugs in the eye.
Novel drug delivery systems have gained major attention which could sustain or control the release of drug for extended period of time as well as increase the stability and bioavailability of therapeutic agents such as proteins, genes and other small molecules. Biodegradable (PLGA, PCL) and non-biodegradable (e.g Vitraset and Retisert) implants provides a platform for sustaining release of drug over several months to years. However, erratic drug release profile for biodegradable implants and requirement of highly invasive eye surgery are few drawbacks. Micro and nanoparticles provide sustained release of encapsulated molecules for weeks to months. However, use of organic solvents such as dichloromethane during preparation denatures and reduces protein efficacy leading to non-effective treatment. Further encapsulation efficiency, controlled particles size, and sterility during preparations are among the other hurdles. Iontophoresis, microneedles, ultrasound based ocular deliver have also been tried, however, the major advances are with the small molecule drugs and still are in investigation stage and needs validations to establish their efficacy and safety. Thus non- or minimally-invasive, controlled, and sustained delivery to the posterior segment is becoming extremely vital with escalating advances in the emerging therapies for retinal degenerations.